WARNING

Hycamtin (topotecan hydrochloride) for Injection should be administered under the supervision of a physician experienced in the use of cancerchemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/m
2
administered as a 30-minute infusion. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional. Binding of topotecan to plasma proteins is about 35%.

RenalImpairment:
In patients with mild renalimpairment (creatinine clearance of 40 to 60 mL/min.), topotecan plasma clearance was decreased to about 67% of the value in patients with normalrenalfunction. In patients with moderate renalimpairment (Cl
cr
of 20 to 39 mL/min.), topotecan plasma clearance was reduced to about 34% of the value in control patients, with an increase in half-life. Mean half-life, estimated in three renally impaired patients, was about 5.0 hours. Dosage adjustment is recommended for these patients (see DOSAGE AND ADMINISTRATION ).

HepaticImpairment:
Plasma clearance in patients with hepatic impairment (serum bilirubin levels between 1.7 and 15.0 mg/dL) was decreased to about 67% of the value in patients without hepatic impairment. Topotecan half-life increased slightly, from 2.0 hours to 2.5 hours, but these hepatically impaired patients tolerated the usual recommended topotecan dosage regimen (see DOSAGE AND ADMINISTRATION ).

DrugInteractions:
Pharmacokinetic studies of the interaction of topotecan with concomitantly administered medications have not been formally investigated.
In vitro
inhibition studies using marker substrates known to be metabolized by human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidinedehydrogenase indicate that the activities of these enzymes were not altered by topotecan. Enzymeinhibition by topotecan has not been evaluated
in vivo
.

CLINICAL STUDIES

Ovarian Cancer

Hycamtin (topotecan hydrochloride) was studied in two clinical trials of 223 patients given topotecan with metastaticovariancarcinoma. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these two studies received an initial dose of 1.5 mg/m
2
given by intravenousinfusion over 30 minutes for 5 consecutive days, starting on day 1 of a 21-day course.

One study was a randomized trial of 112 patients treated with
Hycamtin
(1.5 mg/m
2
/day × 5 days starting on day 1 of a 21-day course) and 114 patients treated with paclitaxel (175 mg/m
2
over 3 hours on day 1 of a 21-day course). All patients had recurrentovariancancer after a platinum-containing regimen or had not responded to at least one prior platinum-containing regimen. Patients who did not respond to the studytherapy, or who progressed, could be given the alternative treatment.

The mediantime to response was 7.6 weeks (range 3.1 to 21.7) with
Hycamtin
compared to 6.0 weeks (range 2.4 to 18.1) with paclitaxel. Consequently, the efficacy of
Hycamtin
may not be achieved if patients are withdrawn from treatment prematurely.

In the crossover phase, 8 of 61 (13%) patients who received
Hycamtin
after paclitaxel had a partial response and 5 of 49 (10%) patients who received paclitaxel after
Hycamtin
had a response (two complete responses).

Small Cell Lung Cancer

Randomized Comparative Study

In a randomized, comparative, Phase 3 trial, 107 patients were treated with
Hycamtin
(1.5 mg/m
2
/day × 5 days starting on day 1 of a 21-day course) and 104 patients were treated with CAV (1000 mg/m
2
cyclophosphamide, 45 mg/m
2
doxorubicin, 2 mg vincristine administered sequentially on day 1 of a 21-day course). All patients were considered sensitive to first-linechemotherapy (responders who then subsequently progressed >/=60 days after completion of first-line therapy). A total of 77% of patients treated with
Hycamtin
and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-linechemotherapy.

The time to response was similar in both arms:
Hycamtin
median of 6 weeks (range 2.4 to 15.7) versus CAV median 6 weeks (range 5.1 to 18.1).

Changes on a disease-related symptomscale in patients who received
Hycamtin
or who received CAV are presented in Table 3. It should be noted that not all patients had all symptoms nor did all patients respond to all questions. Each symptom was rated on a four category scale with an improvement defined as a change in one category from baseline sustained over two courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

small cell lung cancer sensitive disease after failure of first-line chemotherapy. In clinical studies submitted to support approval, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing at least 60 days (in the Phase 3 study) or at least 90 days (in the Phase 2 studies) after chemotherapy (See Clinical Studies Section).

ADVERSE REACTIONS

Data in the following section are based on the combined experience of 453 patients with metastaticovariancarcinoma, and 426 patients with small celllungcancer treated with
Hycamtin
. Table 4 lists the principal hematologic toxicities and Table 5 lists non-hematologic toxicities occurring in at least 15% of patients.

Premedications were not routinely used in patients randomized to
Hycamtin
, while patients receiving paclitaxel received routine pretreatment with corticosteroids, diphenhydramine, and histaminereceptor type 2 blockers.

Premedications were not routinely used in patients randomized to
Hycamtin
, while patients receiving CAV received routine pretreatment with corticosteroids, diphenhydramine, and histaminereceptor type 2 blockers.

Postmarketing Reports of Adverse Events.
Reports of adverse events in patients taking Hycamtin (topotecan hydrochloride) received after market introduction, which are not listed above, include the following:

The LD
10
in mice receiving single intravenous infusions of
Hycamtin
was 75 mg/m
2
(CI 95%: 47 to 97).

DOSAGE AND ADMINISTRATION

Prior to administration of the first course of
Hycamtin
, patients must have a baseline neutrophilcount of >1500 cells/mm
3
and a plateletcount of >100,000 cells/mm
3
. The recommended dose of Hycamtin (topotecan hydrochloride) is 1.5 mg/m
2
by intravenousinfusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of four courses is recommended because tumorresponse may be delayed. The mediantime to response in three ovarianclinical trials was 9 to 12 weeks and mediantime to response in four small celllungcancer trials was 5 to 7 weeks. In the event of severe neutropenia during any course, the dose should be reduced by 0.25 mg/m
2
for subsequent courses. Alternatively, in the event of severe neutropenia, G-CSF may be administered following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration).

PREPARATION FOR ADMINISTRATION

Precautions:
Hycamtin
is a cytotoxic anticancer drug. As with other potentially toxic compounds,
Hycamtin
should be prepared under a verticallaminarflowhood while wearing gloves and protective clothing. If
Hycamtin
solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If
Hycamtin
contacts mucous membranes, flush thoroughly with water.

STABILITY

Unopened vials of Hycamtin (topotecan hydrochloride) are stable until the date indicated on the package when stored between 20° and 25° C (68° and 77° F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of
Hycamtin
diluted for infusion are stable at approximately 20° to 25° C (68° to 77° F) and ambient lighting conditions for 24 hours.

HOW SUPPLIED

Storage
Store the vials protected from light in the original cartons at controlled room temperature between 20° and 25° C (68° and 77° F) [see USP].

Handling and Disposal:
Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.
1-7
There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual
or relative
size.